JPH0717855A - Cerebral function-improving composition, learning ability-enhancing agent, mnemonic agent, dementia-preventing agent, dementia-treating agent, or functional food having cerebral function-improving effect - Google Patents

Abstract

PURPOSE:To provide a functional food improving a cerebral function, thereby useful for the enhancement of learning ability, the increase of mneme and the prevention and treatment of senile dementia, and having a good cerebral function-improving effect. CONSTITUTION:A cerebral function-improving composition comprises one kind or more of n-3 series fatty acids consisting of docosahexaenoic acid, eicosapentaenoic acid and alpha-linolenic acid as an active ingredient and one kind or more of lipolipids selected from the phosphatidyl choline(PC), phosphatidyl ethanolamine(PE), phosphatidyl serine(PS), phosphatidyl inositol(PI) or their liso compounds.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a substance having an effect of improving brain function, that is, a brain function improving composition, and a learning ability enhancer which is a drug embodied using the brain function improving composition. The present invention relates to a memory enhancer, a dementia preventive agent, a dementia therapeutic agent, a functional food having a brain function improving effect, and the like.

[0002]

2. Description of the Related Art In recent years, many researches and studies have been conducted in various fields on materials and methods for improving brain functions such as learning ability, memory ability, dementia, etc., and the results have been announced little by little. According to it, the methods of improving brain function that have been studied so far are the brain energy metabolism improving method of activating the function of cells by efficiently absorbing the nutrients to the brain cells, and improving the blood circulation of the brain. It is roughly divided into cerebral circulation improvement methods that try to supply sufficient nutrients and oxygen to cells, and research is being conducted on drugs and therapeutic methods that have their respective pathological effects. Disease) is recognized as being divided into two types: Alzheimer-type dementia caused by nervous system disorders and cerebrovascular dementia caused by cerebrovascular disorders. Research seems to be under way.

In the former case of Alzheimer-type dementia, it is known that the production of acetylcholine, which is a neurotransmitter, is remarkably reduced as a neurochemical change in the brain, and prevention of this disease and As a therapeutic method, it is performed to restore physiological function by supplementing the lowered metabolism of choline system. For example, PCT patent application publication No. 56-500374 "Method and composition for treating disease by administering lecithin", JP-A-59-167514 "Brain function enhancer composition", JP-A-60. No. 214734, “Neuropathy and chemotaxis therapeutic composition and method”, and the like. That is, by ingesting phosphatidylcholine, which is a choline-containing phospholipid, acetylcholine is supplied to the brain, which is expected to prevent and treat Alzheimer's dementia and other neurological disorders.

Further, phosphatidylethanolamine, which is a kind of phospholipid, is converted into phosphatidylcholine by a methyl group transfer reaction from S-adenosylmethionnin. Therefore, the phosphatidylethanolamine is also expected to be used as a preventive and therapeutic agent for Alzheimer's dementia and other neurological disorders.

In the present invention, docosahexaenoic acid (hereinafter referred to as DHA), which is one of the active ingredients having an effect of improving brain function, is C ₂₂ 11 ₃₂ O ₂ , molecular weight 32.
8.4 g, which is a linear hexaenoic acid having 22 carbon atoms and having a cis double bond at the 4, 7, 10, 13, 16, 19 position,
Its melting point is -44.5 to -44.1 ° C. this is,
It is abundant in fish oils such as herrings and sardines, and in fats and oils contained in krills. Further, it is known that a large amount is contained in cell membranes of central nerves such as the brain, nerves and retina of mammals. Rudin, DO: Biol. Psychiatry, 16 838-850 (1
981), when linseed oil (50-60%) containing a large amount of α-linolenic acid, which is a precursor of DHA, was given to mental and neurotic patients who did not respond to various drug treatments, the symptoms were improved. , It was stated that the symptoms returned when the administration was discontinued. However, it is hard to say that the research in this field is still at the stage of being fully researched and elucidated, both theoretically and in terms of practical application, and in general, it has been confirmed that significant therapeutic effects have been confirmed and the materials that have been commercialized There are few drugs.

As the memory enhancer and the agent for treating senile dementia which have been recently announced, for example, a memory enhancer containing 2- (7-indenyloxymethyl) morpholine or an acid addition salt thereof as an active ingredient (JP-A-56) -123915),
A therapeutic agent for Alzheimer's disease (JP-A-58-12123), characterized by comprising a salt of deferoxamine to which a pharmaceutically acceptable acid is added, H-X-Y-OH (where X and Y are different from each other) , Tyr, or Arg), and a memory-improving agent containing a dipeptide compound (Japanese Patent Application Laid-Open No. 58-170719), 3.7-dihydro-3-
Methyl-1- (5-oxohexyl) -7-propyl-
There is a therapeutic agent for memory disorders containing 1H-purine-2.6-dione as an active ingredient (Japanese Patent Application Laid-Open No. 61-229823) and the like.
T International application (Patent application publication Sho 61-5015
No. 64) is a certain amount. With the aging of society in recent years, the development of such materials and medicines has been earnestly desired not only medically but also socially.

[0007]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention responds to the above-mentioned demand and improves brain function, thereby enhancing learning ability, memory enhancement, prevention and treatment of senile dementia, and brain function. It is intended to embody a functional food having an improving effect. The present inventors have found that docosahexaenoic acid contained in oils obtained from herrings, sardines and the like in a large amount had physiological activity and drug activity, and in marine animals, physiological activity of phospholipids specifically contained in krills in a large amount in marine animals. While conducting research on drug activity and drug activity, a mixed composition of these two kinds of substances has a powerful improvement in learning ability, dementia prevention and treatment effects, in addition to the results of animal tests. These are present as a part of the composition components of plants in the natural world, and have been found empirically to be safe, and as a result, they have found that they are extremely useful as drugs and foods that have the effect of improving brain function. The invention has been completed. According to the present invention, when a mixture of phospholipid and DHA, which can be a precursor of acetylcholine which is a neurotransmitter in the brain, is administered to rats, these mixtures improve learning ability, memory improving effect and prevention of senile dementia. Since it was found from the experimental results that it is effective for treatment and treatment, it is not possible to embody products such as drugs and foods by utilizing these pharmacological effects.

Hereinafter, the above-mentioned pharmacological effects will be described in detail based on experiments. Specifically, the experiment of improving the learning ability and the memory improving effect using the Y maze is performed with the rats of the control group by feeding the rats fed the feed containing the fats and oils containing docosahexaenoic acid and the phospholipids as the active ingredients together with the rats in the control group. Is. That is, in order to examine that a mixture of DHA and phospholipid has an effect of improving learning ability, Wistar rats, a feed containing a mixture of DHA ethyl ester and phospholipid as an active ingredient, and a Y maze are prepared. The rats were placed in the Y maze, and the following experiment was conducted.

[0009] First, as the Wistar rats, a total of 80 male Wistar 4-week-old rats were prepared, each of which was divided into 4 groups of 20 rats, and the test groups were selected according to the kind of the feed to be fed for a predetermined period. Group 4 and control group 1. Next, in the above-mentioned experiment, the test feed divided into the test group 4 and the control group 1 is a feed containing the following components. That is, the compounded feed used in the experiment is composed of the raw materials having the compounding ratios shown in Table 1A and Table 1B, and the fatty acid composition of the fat, which is a component thereof, has four different types as shown in Table 2. Use test feed.

[0010]

[Table 1A]

[0011]

[Table 1B]

[0012]

[Table 2]

[0013]

[Experimental Example 1] {Group in which DHA-containing ethyl ester and phospholipid are mixed}
Of the effect of improving learning ability and memory of 20 male Wistar 4-week-old rats preliminarily reared for 1 week and then mixed with a mixture of ethyl ester containing DHA and phospholipid for 11 weeks (E test in Table 2) Feeding area). After that, the rats are put into individual cages so that the body weight of the rats becomes 85%, and shaping is performed before the main test. Hereinafter, the group of rats fed with the E test feed in this manner is referred to as (E test feed group). The experiment was 20 animals, 5 animals per day in the E test feed group (total of 1 animal per day)
The experiment (00 times) was performed for 18 days, and this was measured.

In this experimental method, the animal is first placed at the starting point. Then, the animal starts exploratory behavior and reaches the selection point after a while, and selects the side with the light and the food or the side without the light and the food. 3 after placing at the starting point
The animals that could reach the side with food within 0 seconds were regarded as the correct answer, and those that took more time and entered the side without food were regarded as the incorrect answer. Animals learn that they can see only the light and start feeding at the lighted side only at the selected point of the Y maze, and their memory ability is examined by repeating this every day. For comparison, instead of the feed containing DHA-containing ethyl ester and phospholipid, a feed containing safflower oil and olive oil (control feed group in Table 2) and DHA.
Rats were bred by setting up a test section fed with a feed containing only the contained ethyl ester (D test feed section in Table 2). The results are shown in FIGS. 1 to 4.

As shown in FIG. 1, on the 18th day from the start of the experiment, the positive reaction rate of the E test feed group reached 75%, and the positive reaction rate of the control test feed group and the D test feed group increased. In comparison, it showed extremely high positive efficiency. Further, FIG. 2 shows the changes in the reaction in the E test feed group, FIG. 3 in the D test feed group, and FIG. 4 in the control feed group. The number of reactions is higher than that of R + (the number of correct reactions), but the E test feed group starts R from around the 5th day.
While R-significantly increased with-, R- hardly decreased in the control test diet group, and therefore the correct answer rate did not increase so much. Further, in the D test feed group in which only the DHA-containing ethyl ester was blended alone, the correct answer rate was increased in the middle. In other words, if the DHA ethyl ester group goes to the side of the light earlier than the control feed group, it will learn that it will receive the food, and will remember it for days. Further, it was found that the effect was enhanced by adding phospholipid to DHA ethyl ester. From the above, it was revealed that (the feed group mixed with DHA-containing ethyl ester and phospholipid) most strongly enhanced the learning effect and memory in the light-dark discrimination feeding behavior performed using the Y maze.

[0016]

[Experimental Example 2] Experiment of improving learning ability and memory improving effect of {group in which DHA-containing triglyceride and phospholipid were mixed} 20 male 4-week-old Wistar rats were preliminarily cultivated for 1 week and then treated with DHA-containing triglyceride for 11 weeks. The animals are fed with a test feed mixed with a mixture of phospholipids (T test feed group in Table 2). After that, the rat weight is 85% for 2 weeks.
The test is carried out after placing them in individual cages so that they become Hereinafter, the group of rats fed with the T-test feed in this manner is referred to as the T-test feed group. Experiment is the T
20 animals 5 times a day in the test feed group (total 1 daily
The experiment (00 times) was performed for 18 days, and this was measured.

In the experimental method, the animal is first placed at the starting point. Then, the animal starts exploratory behavior and reaches the selection point after a while, and selects the side with the light and the food or the side without the light and the food. 3 after placing at the starting point
The animals that could reach the side with food within 0 seconds were regarded as the correct answer, and those that took more time and entered the side without food were regarded as the incorrect answer. For the first time, the animal can see only the light at the selected point in the Y maze and learns that it can take food to the lighted side, and the memory ability is examined by repeating this every day. For comparison, instead of the feed in which DHA-containing triglyceride and phospholipids were mixed, a diet in which safflower oil and olive oil were mixed (control feed group in Table 2) and D
Rats were bred by setting up a test section fed with a feed containing only HA-containing ethyl ester (D test feed group in Table 2). The results are shown in FIGS.

As shown in FIG. 5, on the 18th day from the start of the experiment, the positive reaction rate of the T test feed group reached 78%, and the positive reaction rate of the control test feed group and the D test feed group increased. In comparison, it showed extremely high positive efficiency. In addition, FIG. 6 shows the changes in the reaction in the T test feed group, FIG. 7 in the D test feed group, and FIG. 8 in the control feed group. The number of reactions is higher than that of R + (the number of correct reactions), but for the T-test feed group, R from around the 5th day
While R-significantly increased with-, R- hardly decreased in the control test diet group, and therefore the correct answer rate did not increase so much. Further, in the D test feed group in which only the DHA-containing ethyl ester was blended alone, the correct answer rate was increased in the middle. In other words, if the DHA-containing group goes to the side of the light earlier than the control feed group, it will learn that it will receive the food, and will remember it for days. Further, it was found that the effect was enhanced by adding phospholipid to DHA-containing triglyceride. From the above, it was revealed that (the feed group mixed with DHA-containing triglyceride and phospholipid) most strongly enhances the learning effect and the memory in the light-dark discrimination feeding behavior performed using the Y maze.

[0019]

[Experimental Example 3] Experiment of improving learning ability and memory improving effect of {group containing DHA-containing phospholipid and DHA-containing ethyl ester} 20-week-old male Wistar rats were preliminarily cultivated for 1 week, and then DHA for 11 weeks The test feed (R test feed group in Table 2) mixed with a mixture of the contained phospholipid and the DHA-containing ethyl ester is fed. After that, the rats are put into individual cages so that the body weight of the rats becomes 85%, and shaping is performed before the main test. Hereinafter, the group of rats fed with the R test feed in this manner is referred to as (R test feed group). In the experiment, 5 animals per day in the R test feed group, 20 animals per day (total 100 times of experiments per day) were conducted for 18 days, and this was measured.

In this experimental method, the animal is first placed at the starting point. Then, the animal starts exploratory behavior and reaches the selection point after a while, and selects the side with the light and the food or the side without the light and the food. 3 after placing at the starting point
The animals that could reach the side with food within 0 seconds were regarded as the correct answer, and those that took more time and entered the side without food were regarded as the incorrect answer. Animals learn that they can see only the light and start feeding at the lighted side only at the selected point of the Y maze, and their memory ability is examined by repeating this every day. For comparison, DHA-containing phospholipids and DH
A feed containing safflower oil and olive oil in place of the feed containing A-containing ethyl ester and phospholipid (control feed group in Table 2) and a feed containing only DHA-containing ethyl ester (D test feed group in Table 2) A test section was provided and rats were bred. The results are shown in FIGS. 9 to 12.

As shown in FIG. 9, the positive reaction rate of the R test feed group reached 84% on the 18th day from the start of the experiment, and the positive reaction rate of the control test feed group and the D test feed group increased. In comparison, it showed extremely high positive efficiency. In addition, FIG. 10 shows the changes in the reaction in the R test feed group, FIG. 11 in the D test feed group, and FIG. 12 in the control feed group. The number of reactions is higher than that of R + (the number of correct responses), but in the R test feed group, R− decreases and R + significantly increases from around the 5th day, whereas in the control test feed group, R−. Hardly decreases,
Therefore, the accuracy rate did not rise so much. Also, DH
In the D test feed group in which only the A-containing ethyl ester was blended alone, the correct answer rate increased in the middle. That is, DH
If the A-containing group goes to the side of the light earlier than the control feed group, it will learn that it will receive the food, and will remember it for days. Further, it was found that the effect was enhanced by adding DHA-containing phospholipid to DHA ethyl ester. From the above, (DH
It was found that the feed group in which A-containing phospholipid and DHA-containing ethyl ester were mixed) most strongly enhanced the learning effect and the memory ability in the light-dark discrimination food feeding behavior performed using the Y maze. The docosahexaenoic acid used in the present invention can be used as the acid itself, but is also an ethyl ester, a methyl ester, or a triglyceride, preferably phosphatidylcholine (PC),
Phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (P
Examples thereof include phospholipid type compounds such as I).

As the phospholipid used in the present invention, soybean-derived phospholipid can be used, and egg yolk-derived or krill-derived phospholipid can be used as the phospholipid. Is an unused marine product resource containing a large amount of phospholipids containing a large amount of DHA, and examples thereof include phospholipids extracted from krill, which has abundant resources. However, since the krill phospholipid has a DHA content of about 20%, it is more effective if it is supplemented with higher purity DHA. The mixture of DHA and phospholipid used in the present invention may have a phospholipid content of 0.1% or more, but preferably a phospholipid content of about 10% is used, and the daily intake is 1 mg to 100 g. It is preferable to take 1 mg to 10 g. The mixture of docosahexaenoic acid and its ethyl ester, methyl ester, triglyceride, and docosahexaenoic acid-containing phospholipid and phospholipid according to the present invention can be used as it is as a learning ability enhancer, memory enhancer, dementia treatment or preventive agent. Can also be formulated as a mixture with pharmaceutically acceptable diluents and / or pharmacologically acceptable diluents and / or other pharmacological agents according to pharmaceutical practice.

Further, the composition may be in the form of tablets or packages in dosage units. Examples of such forms that can be taken as a medicine include powders, granules, tablets, dragees, capsules, pills, solutions, ampoules, injections and the like. Also, the formulation means includes the sun contained in the form of a mixture with a pharmaceutically acceptable diluent. Here, as the diluent, for example, an excipient, a bulking agent,
Binders, wetting agents, disintegrating agents, surfactants, lubricants, dispersants, buffers, flavoring agents, flavoring agents, perfumes, preservatives, solubilizing-auxiliaries, solvents, coating agents, etc. are considered. Of course, it is not limited to these. They can also be used as a mixture of one or more of these, and such a pharmaceutically acceptable diluent may be used as a mixture with other pharmacologically active substances. Formulation may be carried out by any known method. For example, the active ingredient may be mixed with a diluent, granulated once, and the composition may be molded into a tablet.

[0024]

Example 1 First, some examples of formulation according to the present invention will be described. * Tablet The ingredients were blended so as to contain the components shown in Table 3 and adjusted according to the tablet formulation. The tablets were coated with sugar, but the invention is not limited to this, and it goes without saying that the tablets may be coated with other suitable materials.

[0025]

[Table 3]

* Hard capsules Hard capsules were obtained with the above-mentioned untabletted powder shape formulation of 600 mg. * Soft capsule docosahexaenoic acid ethyl ester and phospholipid (9:
(1; weight ratio) 300 mg was added with an antioxidant according to a conventional method, and the resulting mixture was filled in a soft capsule to obtain a soft capsule. The purity of DHA used as a drug may be 50% or more in the total fatty acid composition, but is preferably 90% or more.

[0027]

Example 2 Next, an example of the functional food of the present invention will be shown.
The functional food, which is a mixture of docosahexaenoic acid and phospholipid according to the present invention, may be an oil or fat containing 10% or more of docosahexaenoic acid. desirable. Docosahexaenoic acid-containing margarine A docosahexaenoic acid-containing margarine was prepared according to a formulation example shown in Table 4.

[0028]

[Table 4]

Margarine having the above composition was put into a quenching and straining machine to produce it. * Docosahexaenoic acid-containing mayonnaise The docosahexaenoic acid-containing mayonnaise was prepared according to the formulation example shown in Table 5.

[0030]

[Table 5]

A mayonnaise having the above composition was produced with a vacuum stirrer. * Tofu powder containing docosahexaenoic acid 55 g of tofu powder was dissolved in 395 g of water and dissolved well, then put on an open fire to boil and boil for 3 minutes, then turn off the heat, add 50 g of the emulsion of the following composition, and add glucono delta lactone (coagulation Add 1.5 g of agent), stir quickly and cover. The tofu containing docosahexaenoic acid was hardened at room temperature for 1 hour to prepare tofu. * Emulsion composition The emulsion composition was adjusted according to the formulation example shown in Table 6.

[0032]

[Table 6]

* Ice cream containing docosahexaenoic acid 25 parts of triglyceride containing 25% of docosahexaenoic acid, 7.9 parts of skimmed milk powder, 20 parts of sugar, 0.2 parts of stearic acid monoglyceride and 0.2 parts of casein were added, and water was further added. To 100 parts in total, and while stirring, heat to 60 ° C. and mix. The mixed raw materials are homogenized with a homogenizer. Subsequently, it is sterilized by heating at 70 ° C for 30 minutes, and immediately cooled to 0 ° C. The mixture left at that temperature for a whole day and night is vigorously stirred and cooled to -2 ° C with aeration.
Finally, it was cured in a freezer to obtain an ice cream containing docosahexaenoic acid.

[0034]

INDUSTRIAL APPLICABILITY As described above, the present invention enhances brain function or recovers brain damage by a brain function improving composition containing a mixture of docosahexaenoic acid (DHA) and phospholipid as an active ingredient. Yes, by utilizing its pharmacological effect, or commercialized as a raw material of drugs and functional foods, or by mixing it with an appropriate pharmacologically acceptable carrier, excipient, diluent, liquid, powder, It may be commercialized by processing it into a desired form such as granules, tablets, injections, capsules and suppositories. Further, it goes without saying that this agent may be administered orally or parenterally in the above-mentioned form. Needless to say, the dose may be increased or decreased depending on the age, body weight, symptoms, etc. As described above, according to the present invention, when a mixture of docosahexaenoic acid and phospholipid, which is a substance having an effect of improving brain function, is ingested into the human body in the form of a drug or food, its active ingredient enhances the learning ability. As a result, memory will be strengthened. Further, by ingesting the brain function improving composition as a drug or as a food as in the present invention, it is possible to prevent dementia caused by cerebral disorder in advance or to exert an effect for treating various dementia.

[Brief description of drawings]

FIG. 1 is a graph showing a learning process (positive reaction rate%) of a Y-maze light / dark discrimination food feeding behavior experiment of Experimental Example 1 according to the present invention.

FIG. 2 is a graph showing the number of correct reaction times and the number of incorrect reaction reactions of the group in which the DHA-containing ethyl ester and phospholipid were mixed in Experimental Example 1.

FIG. 3 is a graph showing the number of correct responses and the number of incorrect responses of the DHA-containing ethyl ester group in Experimental Example 1.

FIG. 4 is a graph showing the number of correct responses and the number of incorrect responses of a control group in the same Experimental Example 1.

FIG. 5 is a graph showing a learning process (positive reaction rate%) of a Y-maze bright / dark discrimination food feeding behavior experiment of Experimental Example 2.

FIG. 6 is a graph showing the number of correct responses and the number of incorrect responses in the group in which DHA-containing triglyceride and phospholipid were mixed in the same Experimental Example 2.

FIG. 7 is a graph showing the number of correct responses and the number of incorrect responses of the DHA-containing ester group in Experimental Example 2.

FIG. 8 is a graph showing the number of correct response reactions and the number of incorrect response reactions of the control group in Experimental Example 2.

FIG. 9 is a graph showing a learning process (positive reaction rate%) of a Y maze light / dark discrimination food feeding behavior experiment of Experimental Example 3.

FIG. 10 is a graph showing the number of correct responses and the number of incorrect responses of the DHA-containing phospholipid group in Experimental Example 3.

FIG. 11 is a graph showing the number of correct responses and the incorrect response of the DHA-containing ethyl ester group in Experimental Example 3.

FIG. 12 is a graph showing the number of correct responses and the number of incorrect responses of the control group in Experimental Example 3.

Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display area A61K 38/00 // (A61K 31/20 31: 685) (A61K 31/23 31: 685)

Claims (4)

[Claims] 1. An active ingredient comprising at least one or more of n-3 fatty acids such as docosahexaenoic acid, eicosapentaenoic acid and α-linolenic acid, and phosphatidylcholine (PC) and phosphatidylethanolamine (P).
E), phosphatidylserine (PS), phosphatidylinositol (PI) or a cerebral function improving composition comprising at least one or more phospholipids selected from lyso bodies thereof, a learning ability enhancer, a memory enhancer, a dementia preventive ,
A dementia therapeutic agent or a functional food having a brain function improving effect. 2. The brain function-improving composition according to claim 1, wherein the n-3 fatty acid is fatty acid methyl ester and fatty acid ethyl ester, a learning ability enhancer, a memory enhancer, a dementia preventive agent, a dementia therapeutic agent, or A functional food having a brain function improving effect. 3. The brain function improving composition according to claim 1, wherein the n-3 fatty acid is triglyceride, a learning ability enhancer,
A memory enhancer, a dementia preventive agent, a dementia therapeutic agent, and a functional food having a brain function improving effect. 4. The brain function improving composition, learning ability enhancer, memory enhancer, dementia preventive agent according to claim 1, which provides 1 mg to 100 g of the n-3 fatty acid and phospholipid according to claim 1 per day. , A dementia therapeutic agent, or a functional food having a brain function improving effect.